In order to evaluate the link between primary hyperparathyroidism (pHPT) and malignancies, cases subjected to parathyroid adenomectomy (PTX) during 1958-1997 in Sweden were identified by analyzing the National Swedish Cancer Registry. To minimize the influence of confounding by detection, cases with malignant disease diagnosed before or at the same time as pHPT or during the first year after PTX were excluded. Altogether 9782 cases (7642\) were included and followed for up to 40 years. Thus, the study comprises 89 571 person-years of observation. The incidence of malignancies was compared with that in the Swedish population standardized for age, sex, and calendar year. An increased overall incidence of cancer was demonstrated in both genders (standardized incidence ratio (SIR) 1.43, 95% confidence interval (CI) 1.35-1.52). This remain unchanged beyond 15 years after PTX. Breast cancer contributed a quarter of the cancer incidence in women (SIR 1.44, 95% CI 1.25-1.62). An increased risk of kidney (SIR 2.40, 95% CI 1.72-3.25), colonic (SIR 1.46, 95% CI 1.19-1.77), and squamous cell skin cancer (SIR 2.79, 95% CI 2.25-3.43) was found in both genders. The risk of endocrine and pancreas cancer was increased in the minority of patients who had their PTX before the age of 40. We conclude that pHPT is associated with an increased risk of developing malignancies that persists even after PTX. This suggests a causal disassociation with the biochemical derangements caused by parathyroid adenoma, while potentially common etiological mechanisms may include genetic predisposition or acquired disability to withstand environmental influence.
The ETS family transcription factor GABPA is suggested as an oncogenic element, which is further supported by the recent reporting of it as the sole ETS member to activate the mutant TERT promoter in thyroid carcinomas (TC). However, it remains unclear how GABPA contributes to TC pathogenesis. The present study is designed to address this issue. TERT expression was significantly diminished in TERT promoter-mutated TC cells upon GABPA inhibition. Surprisingly, GABPA depletion led to robustly increased cellular invasion independently of TERT promoter mutations and TERT expression. DICER1, a component of the microRNA machinery, was identified as a downstream effector of GABPA. GABPA facilitated Dicer1 transcription while its depletion reduced Dicer1 expression. The mutation of the GABPA binding site in the DICER1 promoter led to diminished basal levels of DICER1 promoter activity and abolishment of GABPA-stimulated promoter activity as well. The forced DICER1 expression abrogated the invasiveness of GABPA-depleted TC cells. Consistently, the analyses of 93 patients with papillary thyroid carcinoma (PTC) revealed a positive correlation between GABPA and DICER1 expression. GABPA expression was negatively associated with TERT expression and promoter mutations, in contrast to published observations in cancer cell lines. Lower GABPA expression was associated with distant metastasis and shorter overall/disease-free survival in PTC patients. Similar results were obtained for PTC cases in the TCGA dataset. In addition, a positive correlation between GABPA and DICER1 expression was seen in multiple types of malignancies. Taken together, despite its stimulatory effect on the mutant TERT promoter and telomerase activation, GABPA may itself act as a tumor suppressor rather than an oncogenic factor to inhibit invasion/metastasis in TCs and be a useful predictor for patient outcomes.
The identification of parathyroid carcinomas is based upon histopathological criteria in which an invasive growth pattern or distant metastasis is demonstrated. A dilemma arises when tumours present with atypical histopathological features but lack direct evidence of malignancy. Recently, reduced expression or loss of the tumour suppressor proteins parafibromin and adenomatous polyposis coli (APC) has been associated with parathyroid malignancy. We report results from APC and parafibromin expression analyses by immunohistochemistry and Western blot in five cases of atypical adenoma, a single case of carcinoma and 54 adenomas without atypical features. Complete loss of APC immunoreactivity and reduced expression of parafibromin was evident in two of the atypical adenomas and in the parathyroid carcinoma. By contrast, all adenomas displayed APC expression, including two cases with hyperparathyroidism 2 gene (HRPT2) mutations and loss of parafibromin expression. We conclude that loss of APC is a frequent molecular event in atypical adenomas and carcinomas, but not in adenomas. Following verification in an independent material, APC could become a valuable tool when assessing parathyroid tumours in the clinical setting. Furthermore, the molecular resemblance of atypical adenomas with carcinoma concerning parafibromin and APC expression indicates that atypical adenomas should be subjects to watchful follow-up.
Except for a lower 25-OH-D level and slightly higher systolic BP and TG levels, patients with mild PHPT without other CV risk factors did not differ from healthy controls as regards biomarkers predicting CV diseases. PTX had an overall positive effect on TG level, BP, and vitamin D status.
ObjectivePrimary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity. The extent of cardiovascular abnormalities in patients with mild-asymptomatic disease is unclear. Using sensitive echocardiographic methods, we compared cardiac structure and function in patients with mild PHPT and in healthy controls, and evaluated the changes after parathyroidectomy (PTX).MethodsIn a prospective case–control design, we studied 51 PHPT patients without any cardiovascular risk factors/diseases and 51 healthy matched controls. Cardiac structure, and systolic and diastolic function were evaluated by echocardiography and Doppler tissue imaging (DTI). Blood pressure (BP) and heart rate were measured.ResultsWe observed no differences in systolic or diastolic function or in cardiac morphology between the PHPT patients and the age-matched healthy controls. The regional peak systolic myocardial velocities (S′) measured with DTI decreased at all sites (P<0.05) after PTX (tricuspid annulus 14.23±1.85 to 13.48±1.79, septal 8.48±0.96 to 7.97±0.85, and lateral 9.61±2.05 to 8.87±1.63 cm/s, part of the mitral annulus). At baseline, systolic BP was higher in patients compared to controls (127.6±17.1 vs 119.6±12.6 mmHg, P<0.05). After PTX, both systolic (127.6±17.1 vs 124.6±16.6 mmHg, P<0.05) and diastolic (80.3±9.6 vs 78.4±8.6 mmHg, P<0.05) BP decreased.ConclusionsOur results indicate that patients with PHPT without cardiovascular risk factors have a normal global systolic and diastolic function and cardiac morphology. BP and the systolic velocities were marginally reduced after PTX, but reflected the values of the control group. Our findings warrant further investigation of the clinical and prognostic significance of these possibly disease-related inotropic effects.
In this study, we genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated in our institution during 2005–2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P<0.001). Further analysis of 21 LPTAs revealed low MIB1 proliferation index (0.1–1.5%), MEN1 mutations in five cases, and one HRPT2 (CDC73) mutation. Total or partial loss of parafibromin expression was observed in ten tumors, two of which also showed loss of APC expression. Using array CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%), and loss in 11q (33%). Totally, 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11, and 15q and gains in 3q, 5, 7p, 8p, 16q, 17p, and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes most frequently gain of 5 and loss of chromosome 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r=0.48, P=0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.